Despite extensive research, the etiology of Crohn's inflammatory bowel disease remains unknown with possible suggestions attributed to genetic susceptibility, infectious agents, immune dysfunction, and various environmental agents. A number of clinical studies have demonstrated an increased intestinal permeability in Crohn's disease patients and in their first-degree relatives. Enhanced mucosal permeability is also a predictive factor of disease recurrence. Thus, a primary disorder of intestinal barrier function constitutes a potential disease factor in the pathogenesis. We have identified a novel homeostatic regulator of intestinal permeability that is actively produced and secreted by enteric glial cells. We propose that s-nitrosoglutathione regulates intestinal barrier function via transnitrosylation of epithelial tight-junction associated proteins. Transnitrosylation is a signaling mechanism involving post-translational modification analogous to protein phosphorylation and acetylation. We hypothesize that aberrant s-nitrosoglutathione homeostasis constitutes a disease mechanism in Crohn's disease resulting in intestinal barrier dysfunction. This view is supported by our preliminary findings that s-nitrosoglutathione restores intestinal barrier function in biopsies from Crohn's disease patients but not in control patients without inflammatory bowel disease. The identification of s-nitrosoglutathione as a glial-derived, small, soluble molecule that protects epithelial-barrier integrity represents a significant advance in the understanding of the cellular interactions that underlie intestinal barrier function. These findings may help in the development of novel therapies for pathologies, such as Crohn's disease, that are associated with inflammatory barrier dysfunction. PUBLIC HEALTH RELEVANCE: Barrier functions across epithelia and endothelia are essential for homeostatic tissue regulation. We identified s-nitrosoglutathione as a novel regulator of intestinal barrier function. We hypothesize that aberrant homeostasis of s-nitrosoglutathione constitutes a new disease mechanism in Crohn's disease. We plan to investigate whether this finding offers a novel approach to therapy for inflammatory permeability disorders.